Active methylene compounds in a very effective approach to 3-substituted isobenzofuranones through tandem aldol/lactonization reactions Antonia Di Mola b, * , Gianluca Croce c , Vijaykumar More a , Paolo De Caprariis b , Rosanna Filosa b , Antonio Massa a, * a Dipartimento di Chimica e Biologia, Universit a di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy b Dipartimento di Scienze Farmaceutiche e Biomediche, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy c DISIT-Universita’ del Piemonte Orientale, Viale T. Michel 11,15121 Alessandria, Italy article info Article history: Received 3 March 2012 Received in revised form 27 April 2012 Accepted 21 May 2012 Available online 27 May 2012 Keywords: Phthalides Tandem reactions Aldol addition Active methylene compounds abstract In this article we describe a new accessible methodology for the synthesis of isobenzofuran-1(3H)-ones. In this process we exploited an effective, economic, useful and environmentally benign K 2 CO 3 catalyzed, solvent-free one-pot tandem aldol-lactonization reaction between active methylene compounds and methyl 2-carboxy benzaldehyde. A particularly simple work-up and purification procedure are additional advan- tages addressed to a general green chemistry approach to this important class of heterocyclic compounds. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Phthalides [isobenzofuran-1(3H)-ones] are integral parts of many naturally occurring substances and they have a wide range of medi- cinal properties. 1 In particular, 3-substituted phthalides are vital heterocyclic motifs in many bioactive compounds, such as iso- coumarins, anthraquinones, anthracyclines and several alkaloids. 2a Typical examples are typhaphthalide, 2b catalpalactone, 2c vermista- tin, 2d isopestacin 2e isoochracin and herbaric acid. 2f They possess a wide range of biological activities, which include antibacterial, an- ticonvulsant and anti-HIV. 3a,b Phthalides also serve as valuable syn- thetic intermediates into the synthesis of several alkaloids 4a (e.g., the convulsant alkaloid biculline), 4b and isoindolinones. 4c In view of their importance, various methods have been developed for the synthesis of phthalides [isobenzofuran-1(3H)-ones]. These methods include cyclization reactions catalyzed by strong acids, such as trifluoroacetic acid 5a and trifluoromethanesulfonic acid 5b or strong bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 5c,d sodium hydroxide and potassium hydroxide. 5e-g Nucleophilic addition of alkyl or aryl or- ganometallic compounds on appropriately substituted phthalalde- hydic acids and its derivatives, 6a photochemical rearrangements, 6b intramolecular cyclization, 6c Tischenko reaction 6d and condensation reactions catalysed by ZrOCl 2 7a are also used in the synthesis of 3- substituted phenylphthalides. Transition metal complexes yield 3- aryl and 3-alkenyl phthalides through catalyzed ketone hydro- acylation and cascade addition/intramolecular cyclization processes. 8 Chiral rhodium catalysts provided an asymmetric version of this reaction, 8e while one organo-catalytic approach has been described. 9 Conversely, due to the biological importance of chiral 3-substituted phthalides, chiral auxiliaries and resolutions of racemates have been intensively explored to develop asymmetric synthesis. 10 Nevertheless relatively few methods focus on the synthesis of isobenzofuran-1(3H)-ones, substituted in the 3-position with 1,3- dicarbonyl groups. Although these derivatives are particularly useful in the synthesis of important bioactive compounds, such as isopestacin or herbaric acid, 5d all these methods involve high temperature, 7b,c the use of transition metals or harmful acids or bases, and show rather limited scope and selectivity. Given the ever increasing necessity of new environmentally friendly methodologies for the synthesis of valuable compounds, herein we report a direct and efficient one-pot tandem aldol- lactonization reaction for the preparation of 3-substituted iso- benzofuran-1(3H)-ones, reacting malonates, diketones, b-ketoesters and nitroalkanes as model nucleophiles under solvent free conditions and in the presence of catalytic amount of the inexpensive K 2 CO 3 . 2. Results and discussion The aldol addition of readily enolizable 1,3-dicarbonyl compounds to aldehydes is very difficult to achieve, and very few applications are * Corresponding authors. Tel.: þ39 089 969565; fax: þ39 089 969603; e-mail address: amassa@unisa.it (A. Massa). Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2012.05.079 Tetrahedron 68 (2012) 6146e6151